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Abstract:

The invention relates to a compound of formula I
##STR00001##
wherein R1, R2 and R3 are identical or different and each
is H or alkyl of 1-6 carbon atoms, R4 is H or methyl, R5 is
phenyl or chlorophenyl, and/or physiologically acceptable salts thereof
and its use in compositions, especially topical, cosmetic and/or personal
care compositions, and compositions containing said compound.

Claims:

1) Composition for topical use comprising a compound of formula of I
##STR00009## wherein R1, R2 and R3 are identical or
different and each is H or alkyl of 1-6 carbon atoms, R4 is H or
methyl, R5 is phenyl or chlorophenyl, and/or physiologically
acceptable salts thereof and one or more topically acceptable vehicles.

2) Composition according to claim 1 wherein the compound of formula I is
5-(7-methoxy-3,3-dimethyl-2,3-dihydro-1-benzoxepin-5-yl)-3-methyl-penta-2-
,4-dienoic and/or a physiologically acceptable salt thereof.

3) Composition for topical use comprising a) active ingredient according
to claim 1, b) one or more skin-tolerated vehicles, and c) optionally one
or more further active compounds having a skin-care and/or
inflammation-inhibiting action.

4) Composition according to claim 1, wherein the active ingredient is
contained in said composition in an amount of 0.00001 percent by weight
to 10 percent by weight.

5) Composition according to claim 1, comprising at least one further
skin-care ingredient and at least one carrier which is suitable for
topical applications.

6) Composition according to claim 5, comprising as a further skin-care
ingredient ectoine, preferably in an amount of 0.01 to 10 percent by
weight, more preferably 0.1 to 5 percent by weight and especially 0.1 to
2 percent by weight.

7) A composition according to claim 1, which is a cosmetic composition.

8) A method for the prophylaxis and/or treatment of skin diseases which
are associated with defective keratinisation relating to differentiation
and cell proliferation, in particular for the treatment of acne vulgaris,
acne comedonica, polymorphic acne, acne rosaceae, nodular acne, acne
conglobata, age-related acne, acne occurring as a side effect, such as
acne solaris, medicament-related acne or acne professionalis, for the
treatment of other defects of keratinisation, in particular ichthyosis,
ichthyosiform states, Darier's disease, keratosis palmoplantaris,
leukoplakia, leukoplakiform states, skin and mucosal (buccal) eczema
(lichen), for the treatment of other skin diseases which are associated
with defective keratinisation and have an inflammatory and/or
immunoallergic component, and in particular all forms of psoriasis
relating to the skin, mucous membranes and finger- and toenails, and
psoriatic rheumatism and skin atopy, such as eczema, or respiratory
atopy, or also hypertrophy of the gums comprising administering to a
subject in need thereof a composition according to claim 1.

10) A method for the care, preservation or improvement of the general
state of the skin or hair, comprising administering to a subject in need
thereof a composition according to claim 1.

11) A method for skin lightening and/or skin whitening, comprising
administering to a subject in need thereof a composition according to
claim 1.

12) A method for skin lightening and/or skin whitening, comprising
administering to a subject in need thereof a composition according to
claim 1.

13) A method for the prophylaxis against or reduction of skin unevenness,
such as wrinkles, fine lines, rough skin or large-pored skin comprising
administering to a subject in need thereof a composition according to
claim 1.

14) A method for the prophylaxis against time- and/or light-induced
ageing processes of the human skin or human hair, in particular for
prophylaxis against dry skin, wrinkle formation and/or pigment defects,
and/or for the reduction or prevention of the harmful effects of UV rays
on the skin comprising administering to a subject in need thereof a
composition according to claim 1.

Description:

[0001] The present invention relates to a indole compound of formula I and
its use in compositions, especially topical, cosmetic and/or personal
care compositions, and compositions containing said compound.

[0002] The human skin is subject to certain ageing processes, some of
which are attributable to intrinsic processes (chronoageing) and some of
which are attributable to exogenous factors (environmental, for example
photoageing). In addition, temporary or even lasting changes to the skin
picture can occur, such as acne, greasy or dry skin, keratoses, rosaceae,
light-sensitive, inflammatory, erythematous, allergic or
autoimmune-reactive reactions, such as dermatosis and photormatosis.

[0003] The exogenous factors include, in particular, sunlight or
artificial radiation sources having a comparable spectrum, and compounds
which can be formed by the radiation, such as undefined reactive
photoproducts, which may also be free-radical or ionic. These factors
also include cigarette smoke and the reactive compounds present therein,
such as ozone, free radicals, for example the hydroxyl free radical,
singlet oxygen and other reactive oxygen or nitrogen compounds which
interfere with the natural physiology or morphology of the skin.

[0004] The influence of these factors can result, inter alia, in direct
damage to the DNA of the skin cells and to the collagen, elastin or
glycosaminoglycan molecules of the extracellular matrix, which are
responsible for the strength of skin. In addition, the signal
transduction chains, which are terminated by the activation of
matrix-degrading enzymes, may be affected. Important representatives of
these enzymes are the matrix metalloproteinases (MMPs, for example
collagenases, gelatinases and stromelysins), whose activity is
additionally regulated by TIMPs (tissue inhibitors of matrix
metalloproteinases).

[0005] The consequences of the above-mentioned ageing processes are
thinning of the skin, weaker interlacing of epidermis and dermis, and a
reduction in the number of cells and the supplying blood vessels. These
results in the formation of fine lines and wrinkles, the skin becomes
leathery, and pigment defects can occur.

[0006] The same factors also act on hair, where damage can likewise occur.
The hairs become brittle, less elastic and dull. The surface structure of
the hairs is damaged.

[0007] Cosmetic or dermatological care products having properties which,
are claimed to counter the processes described or comparable processes or
reduce or reverse the harmful consequences thereof are frequently
distinguished by the following specific
properties--free-radical-scavenging, antioxidative,
inflammation-inhibiting or humectant. They prevent or reduce, inter alia,
the activity of matrix-degrading enzymes or regulate the new synthesis of
collagen, elastin or proteoglycans.

[0008] The above-mentioned ageing processes result in a thinning of the
skin, the decrease of serration between epidermis and dermis, reduction
of the cell number as well as the reduction of the supplying blood
vessels. These processes are accompanied by the formation of lines and
wrinkles, the skin becomes leather-like and/or shows pigmentary
abnormalities.

[0009] Those factors also effect the status of the hair, resulting as well
in a damage of the hair, especially damages in the surface of the hair
that lead to brittleness and the loss of elasticity and gloss of the
hair.

[0010] Care products and/or cosmetic products with properties that shall
counteract against the described or similar processes and/or that shall
reverse the damaging results often sure one or more of the following
properties: free radical scavenging, anti-oxidative, anti-inflammatory
and/or moisturising. Preferably, they block or reduce the activity of the
matrix-disintegrating enzymes or control the denovo-synthesis of
collagen, elastin and/or proteoglycans.

[0011] The use of antioxidants or free-radical scavengers in cosmetic
compositions is adequately known per se. Thus, the use of the
antioxidative vitamin E in sun-screen formulations is usual.
Nevertheless, the effect achieved is even here well short of the
hoped-for effect.

[0012] Vitamin A and vitamin-A derivatives, such as retinoic acid, retinol
and retinol esters, act on the differentiation of epithelial cells and
are therefore employed for the prophylaxis and treatment of numerous
phenomena which impair the skin state, for example use against acne,
psoriasis, senile keratosis, skin discoloration and wrinkles has been
described (cf., for example, WO 93/19743 and WO 02/02074).

[0013] However, a skin-irritant effect of retinol and derivatives is also
described in the literature (for example WO 94/07462). These side effects
restrict the use of retinol to narrowly limited areas, it being necessary
to avoid overdosing. There is therefore a demand for active ingredients
which have a retinol-like spectrum of action, but do not have the side
effects described or at least only do so in reduced form.

[0014] The compound for use according to the instant invention has the
formula I

##STR00002## [0015] wherein [0016] R1, R2 and R3 are
identical or different and each is H or alkyl of 1-6 carbon atoms, [0017]
R4 is H or methyl, [0018] R5 is phenyl or chlorophenyl, [0019]
and physiologically acceptable salts thereof.

[0021] The compound of formula I can be used as free acid but also as one
of its salts with organic or inorganic bases, of the salts formed with
metals and in particular alkali, alkaline earth and transition metals
(such as sodium, potassium calcium, magnesium or aluminium) or with
bases, such as ammonia or secondary or tertiary amines (such as
diethylamine, triethylamine, piperidine, piperazine or morpholine), or
with basic amino acids or with osamines (such as meglumine) or with
aminoalcohols (such as 3-aminobutanol and 2-aminoethanol).

[0022] In a preferred embodiment of the invention the compound for use
according to the instant invention is a compound of sub-formulae Ia to
Ih, which conform to the formula I and in which the radicals not
designated in greater detail have the meaning indicated for the formula
I, but in which,

in Ia R1 is H or alkyl of 1-4 carbon atoms in Ib R1 is H,
methyl, ethyl, n-propyl, isopropyl or isobutyl, in Ic R2 is H,
methyl or ethyl,

in Id R2 is H,

[0023] in Ie R2 is methyl or ethyl, in If R3 is H, methyl or
ethyl,

in Ig R3 is H,

[0024] in Ih R3 is methyl or ethyl.

[0025] Furthermore, particular preference is given to all physiologically
compatible salts of the compounds which come under one or more of
formulae I, Ia, Ib, Ic, Id, Ie, If, Ig and/or Ih.

[0026] In a specifically preferred embodiment of the invention the
compound for use according to the instant invention is
2-Phenyl-2-(1-isobutyl-2-methyl-3-ethoxycarbonyl-5-indolyloxy)-propionic
acid and/or a physiologically acceptable salts thereof.

[0027] The compound of formula I has been previously disclosed in U.S.
Pat. No. 4,069,338, the whole disclosure of which is hereby incorporated
to the present application by reference. According to U.S. Pat. No.
4,069,338 the compound of formula I is effective to lower the cholesterol
level in the product of mammals.

[0028] Suprisingly, it has been found by the present invention that the
compound of formula I is a peroxisome proliferator-activated receptors
(PPAR) ligand, in particular PPAR-alpha and -gamma activator.

[0029] For compounds acting via "PPAR activation" it has been described
that they may be usable as anti-ageing agents.

[0030] It has been shown that PPAR-alpha activator are responsible for
epidermal differentiation (increased levels of filaggrin and involucrin).
PPAR ligands like Oleic acid, linoleic acid and clofibrate accelerated
the development of the stratum corneum and epidermal barrier in fetal
skin explants derived from rats [Gunther Weindl et al., Drugs 2005, 65
(14), 1919-1934].

[0031] PPAR-alpha agonists causes reduced inflammation via the reduction
of interleukin-1 alpha (IL-1a), also PPAR-alpha-induced reduction of
IL-1alpha could result in less melanin being produced and thus
incorporated per cell [J. W. Wiechers et al., International Journal of
Cosmetic Science, 2005, 27, 123-132].

[0032] PPAR activators like Clofibrate increases the expression of
profilaggrin, a major constituent of keratohyalin granules, increases the
processing of profilaggrin to filaggrin, and increases the expression of
loricrin, a key structural protein of the cornified envelope. Furthermore
they induced differentiation in human keratinocyte cultures, as indicated
by increased protein and m-RNA levels of 2 differentiation-specific
proteins: involucrin and transglutaminase. Similar to other inducers of
differentiation, such as vitamin D derivates and retinoic clofibrate
inhibits keratinocyte growth and proliferation in vitro and in vivo
[Hanley K, et al., J Invest Dermatol 1998 April; 110 (4): 368-75 and
Komuves L G, J Invest Dermatol 2000 September; 115 (3): 353-60]

[0033] PPAR-alpha might be important for the development of the epidermis
during late embryogenesis, but dispensable for renewal of the epidermis
in the adult animal [L. Michalik, W. Wahli, Biochimica et Biophysica Acta
1771 (2007) 991-998].

[0038] Reduced inflammation via the reduction of interleukin-1 alpha
(IL-a), therefore is skin tanning as a reaction to UV-induced
irradiation. In the short term, upregulating the p38 pathway leads to
increased tyrosinase production. In the long-term frame, inflammatory
cytokines such as IL-alpha act in a communicative way on melanocytes that
also increases tyrosinase levels. PPAR-alpha-induced reduction of
IL-1alpha could therefore result in less melanin being produced and thus
incorporated per cell [J. W. Wiechers et al., International Journal of
Cosmetic Science, 2005, 27, 123-132]

[0041] TNF-α released by injured epidermal keratinocytes activates
stress-associated protein kinase (SAPK) and induces AP-1 binding to the
PPARδ (PPAR-delta or PPAR-beta) promoter and transcription of
PPARδ target genes. TNF-α also triggers production of
endogenous PPARδ ligands, which activate PPARδ in
keratinocytes and macrophages.

[0042] PPARδ activation helps maintain a sufficient number of
keratinocytes for re-epithelialization by improving apoptosis resistance
through expression of integrin-linked kinase (ILK) and
3-phosphoinositide-dependent kinase (PDK), as well as via activation of
the PKB/Akt-1 survival pathway. The initial inflammatory signals that
stimulate PPARδ are countered by TGF-β1/Smad3-mediated
suppression of PPARδ in the late re-epithelialization/remodeling
stage. This suppression occurs via Smad3/4 complex-mediated abrogation of
AP-1 activity. In addition, TGF-β1 released by dermal wound
fibroblasts increases macrophage numbers and stimulates ECM production
for wound remodelling [L. Michalik, W. Wahli, Biochimica et Biophysica
Acta 1771 (2007) 991-998]

[0043] PPAR activators are the new mechanism of action for skin lightening
and/or whitening. Activators of PPAR receptor are known as a skin
whitening agent. Binding of activators to PPAR-gamma may reduced the
melanogenesis. Binding to PPAR-gamma in turn results in less tyrosinase
being formed. This in turn leads to reduced melanogenesis both in vitro
and in vivo because the compound of formula I binds not only to
PPAR-gamma but also to PPAR-alpha.

[0044] Binding of ligand to the nuclear receptor PPAR may lead to release
of BCL-6, a transcriptional repressor of inflammation. This may result in
decreased expression of inflammatory cytokine genes, reduced
inflammation, and a decrease in atherosclerosis [L. Michalik, W. Wahli,
Biochimica et Biophysica Acta 1771 (2007) 991-998]

[0046] Owing to the constantly increasing demand for active ingredients
for the preventative treatment of human skin and human hair against
ageing processes and harmful environmental influences, the object of the
present invention was to provide novel active ingredients which exhibit
the effects already mentioned at the outset, are sufficiently oxidation-
and photostable and can readily be formulated. The compositions prepared
therewith should furthermore have as far as possible a low irritation
potential for the skin, as far as possible have a positive influence on
water binding in the skin, retain or increase skin elasticity and thus
promote smoothing of the skin. In addition, they should preferably create
a pleasant skin feeling on application to the skin. Preferably, a new
active ingredient preferably shows one or more properties, selected from
the group consisting of anti-ageing, anti-inflammatory, wrinkle
preventing and wound healing properties. Preferably, it can be employed
in products for capillary fragility treatment and/or prophylaxis,
products for the treatment and/or prophylaxis of can, products for the
treatment and/or prophylaxis of psoriasis, products for the treatment
and/or prophylaxis of cellulite and/or Products for treatment and/or
prophylaxis of grey hair.

[0047] It is known that PPAR-gamma agonists are involved in adipogenesis
[Am J Physiol Endocrinol Metab 293:E1159-E1168, 2007]. It is also known
that the development of adipocytes located around hair follicles in the
fetal pig. The relationship between hair follicle development and
adipocyte formation in the pig hypodermis was studied by Hausman G J et
al [J. Animal Sci. 1982. 54:1286-1296]. They show that the development of
hair follicle adipose lobules in the pig is associated temporally and
spatially with hair follicle and sweat gland growth and development [J.
Animal Sci. 1982. 54:1286-1296]. Accordingly the compound of formula I
supposed to be involved in fat cells modulation and so, in hair follicle
development.

[0048] The compound of formula I for use according to the instant
invention is a novel active ingredient for the above discussed uses.
Preferably, the compound of formula I for use according to the invention
has advantageous properties, such as improved handling properties,
improved stability properties and/or an advantageous profile of
activation of PPAR-alpha and -gamma receptors.

[0049] The compound of formula I is in particular useful as anti-ageing,
anti-inflammatory, acne and skin-whitening active and hair growth
regulator ingredient, more particular as growth promoting agent, in
dermatological and cosmetic compositions (alone or in combination with
other actives). Therefore, the invention relates to the use of the
compound of formula I for such purposes. Especially preferred is the use
of the compound of formula I as skin lightening and/or skin whitening
agent.

[0050] The invention also relates to the use of the compound of formula I
in the preparation of cosmetic ingredients for the use as anti-ageing,
anti-inflammatory and for the treatment of acne, inducing or stimulating
of hair growth and retarding hair loss and treatment of hyperpigmentation
or for regulation of pigmentation (depigmentation).

[0051] The compound of formula I has been tested in vitro and shown
increased expression of epidermal differentiation proteins, which also
are known in the literature as indicators of improvement in skin
condition and overall skin health [own unpublished results]

[0052] The term "dermatologically acceptable", as used herein, preferably
means that the composition or components described suitable for use in
contact with human skin without risk of toxicity, incompatibility
instability, allergic response, and the like.

[0053] All terms such as "skin ageing", "signs of skin ageing", "topical
application", and the like are preferably used in the sense in which they
are generally and widely used in the art of developing, testing and
marketing cosmetic and personal care products.

[0054] The term "cosmetic composition" or preferably more briefly just
"composition" in accordance with the present invention preferably relates
to a formulation that can be used for cosmetic purposes, purposes of
hygiene and/or as a basis for delivery of one or more pharmaceutical
ingredients. It is also possible that these formulations are used for two
or more of these purposes at one time. Thus, the terms "cosmetics"
"cosmetic composition" and/or "composition" as used herein, preferably
include without limitation, lipstick, mascara, rouge, foundation, blush,
eyeliner, lipliner, lip gloss, facial or body powder, sunscreens and
blocks, nail polish, mousse, sprays, styling gels, nail conditioner,
whether in the form of creams, lotions, gels, ointments, emulsions,
colloids, solutions, suspensions, compacts, solids, pencils, spray-on
formulations, brush-on formulations and the like. "Personal care
products" preferably include, without limitation, bath and shower gels,
shampoos, conditioners, cream rinses, hair dyes and coloring products,
leave-on conditioners, sunscreens and sunblocks, lip balms, skin
conditioners, cold creams, moisturizers, hair sprays, soaps, body scrubs,
exfoliants, astringents, depilatories and permanent waving solutions,
antidandruff formulations, antisweat and antiperspirant compositions,
shaving, preshaving and after shaving products, moisturizers, deodorants,
cold creams, cleansers, skin gels, rinses, whether in solid, powder,
liquid, cream, gel, ointment, lotion, emulsions, colloids, solutions,
suspensions, or other form. "Pharmaceutical preparations" in accordance
with the present invention preferably include, without limitation,
carriers for dermatological purposes, including topical and transdermal
application of pharmaceutically active ingredients. These can be in the
form of gels, patches, creams, nose sprays, ointments, lotions,
emulsions, colloids, solutions, suspensions, powders and the like.
Compositions in accordance with the invention preferably include
cosmetics, personal care products and pharmaceutical preparations.

[0055] The terms "skin ageing" or "signs of skin ageing" preferably
include, but are not limited to, all outward visibly and tactilely
perceptible manifestations as well as any other macro or micro effects
due to skin ageing. Such signs may be induced or caused by intrinsic
factors or extrinsic factors, e.g. chronological ageing and/or
environmental damage. The signs may result from processes which
preferably include, but are not limited to, the development of textural
discontinuities, such as wrinkles and coarse deep wrinkles, skin lines,
crevices, bumps, large pores (e.g. associated with adnexal structures
such as sweat gland ducts, sebaceous glands, or hair follicles), or
unevenness or roughness of the skin, loss of skin elasticity (loss and/or
in activation of functional skin elastin), sagging (including puffiness
in the eye area and jowls), loss of skin firmness, loss of skin
tightness, loss of skin recoil from deformation, discoloration (including
(black) under eye circles), blotching, sallowness, sallowness,
hyperpigmented skin regions such as age spots and freckles, keratoses,
abnormal differentiation, hyperkeratinization, elastosis, collagen
breakdown, and other histological changes in the stratum corneum, dermis,
epidermis, the skin vascular system (e.g., telangiectasia or spider
vessels), and underlying tissues, especially those proximate to the skin.
Particularly preferred in accordance with the present invention, the
signs of skin aging are wrinkles and the compositions of the present
invention are, in certain preferred embodiments, useful in fighting,
treating or preventing wrinkles.

[0056] As used herein, prophylactically regulating a skin condition
preferably includes delaying, minimizing and/or preventing visible and/or
tactile discontinuities in skin (e.g., texture irregularities in the skin
which may be detected visually or by feel), including signs of skin
aging.

[0057] As used herein, therapeutically regulating skin condition
preferably includes ameliorating, e.g., diminishing, minimizing and/or
effacing, discontinuities in skin, including signs of skin aging. Some of
the products produced using the compositions of the present invention and
indeed the compositions themselves may be used for prophylactically or
therapeutically regulating a skin condition.

[0058] Some of the products and compositions of the present invention are
useful for improving skin appearance and/or feel of skin exhibiting signs
of skin aging. For example, preferred compositions of the present
invention are useful for regulating the appearance of skin conditions by
providing an immediate visual improvement in skin appearance following
application of the composition to the skin. Generally speaking,
compositions of the present invention which further contain particulate
materials will be most useful for providing the immediate visual
improvement.

[0059] Some of the compositions of the present invention may also provide
additional benefits, including stability, absence of significant
(consumer-unacceptable) skin irritation, anti-inflammatory activity and
good aesthetics.

[0060] In certain preferred aspects, the present invention is useful for
improving the physiological state and/or the physical appearance of human
skin, in particular to reduce the signs of skin aging that are generated
by sun exposure, physical and hormonal stress, abrasion, nutritional
effects and other similar causes. The compositions may often be used to
prevent the signs of aging and/or to treat them in order to afford the
consumer who uses them, a more youthful appearance.

[0061] Accordingly, the instant invention more preferably relates to:

A composition, preferably a non-therapeutic composition comprising the
compound of formula I and/or a salt thereof.

[0062] A composition for topical use comprising

i) the compound of formula I and/or a salt thereof, ii) one or more
skin-tolerated vehicles, and optionally iii) one or more further active
compounds having a skin-care and/or inflammation-inhibiting action.

[0063] A composition for topical use comprising

i) the compound of formula I and/or a salt thereof, ii) one or more
skin-tolerated vehicles, and optionally iii) one or more further active
compounds having a skin-care and/or inflammation-inhibiting action.

[0064] A composition as described above/below, wherein the compound of
formula I is contained in said composition in an amount of 0.00001
percent by weight to 10 percent by weight, preferably in an amount of
0.001 percent by weight to 10 percent by weight, more preferably in an
amount of 0.1 percent by weight to 10 percent by weight, even more
preferably 0.001 percent by weight to 5 percent per weight and especially
0.1 percent by weight to 5 percent by weight.

[0065] A composition comprising the compound of formula I and at least one
further skin-care ingredient and at least one carrier which is suitable
for topical applications.

[0066] Use of the compound of formula I for the manufacture of a
composition, preferably a non-therapeutic composition and especially
preferably a cosmetic composition or topical composition.

[0067] Use of the compound of formula I for the preparation of a
composition which is suitable for the prophylaxis and/or treatment of
skin diseases which are associated with defective keratinisation relating
to differentiation and cell proliferation, in particular for the
treatment of acne vulgaris, acne comedonica, polymorphic acne, acne
rosaceae, nodular acne, acne conglobata, age-related acne, acne occurring
as a side effect, such as acne solaris, medicament-related acne or acne
professionalis, for the treatment of other defects of keratinisation, in
particular ichthyosis, ichthyosiform states, Darier's disease, keratosis
palmo-plantar's, leukoplakia, leukoplakiform states, skin and mucosal
(buccal) eczema (lichen), for the treatment of other skin diseases which
are associated with defective keratinisation and have an inflammatory
and/or immunoallergic component, and in particular all forms of psoriasis
relating to the skin, mucous membranes and finger- and toenails, and
psoriatic rheumatism and skin atopy, such as eczema, or respiratory
atopy, or also hypertrophy of the gums.

[0068] Use of the compound of formula I for the care, preservation or
improvement of the general state of the skin or hair.

[0069] Use of the Compound for hair care and/or hair follicle development.

[0070] Use of the compound of formula I for the prophylaxis against or
reduction of skin unevenness, such as wrinkles, fine lines, rough skin or
large-pored skin.

[0071] Use of the compound of formula I for the prophylaxis against time-
and/or light-induced ageing processes of the human skin or human hair, in
particular for prophylaxis against dry skin, wrinkle formation and/or
pigment defects, and/or for the reduction or prevention of the harmful
effects of UV rays on the skin.

[0072] Preferably, the compound of formula I and the compositions
containing it preferably appear to have a benefit in tissue regeneration.
This is believed to be due to their ability to modulate and preferably
stimulate the production of certain advantageous biomolecules, including,
but not limited to, collagen I, fibronectin, collagen IV and/or
hyaluronic acid, in skin cells.

[0073] Thus, the compound of formula I and the compositions containing it
can preferably be used to improve the visible signs of ageing in human
skin, including fine lines, wrinkles, enlarged pores, roughness, dryness,
and other skin texture defects such as the stretchmarks (as caused by
pregnancy, trauma or other influences) bags under the eyes, also called
"puffy eyes" and dark (under eye) circles, both preferably caused by
thinning of the skin, insufficient blood circulation and/or slack tissue,
especially on repeated topical application.

[0074] Thus, further subjects of the instant invention preferably
comprise:

[0075] A method and/or a composition for reducing the visible signs of
ageing, preferably for reducing the visible signs of ageing of the skin
and/or hair, in an animal, preferably the human animal comprising:

applying to the animal showing signs of ageing, preferably to the portion
of the skin and/or hair showing signs of ageing, a composition comprising
the compound of formula I at least once a day for a period of time at
least sufficient to provide a reduction of the visible signs of ageing,
preferably the visible signs of ageing of the skin and/or hair. The
period of time at least sufficient to provide the reduction of the
visible signs of ageing generally is between one day and 12 months,
preferably three days and six months, more preferably between two weeks
and two months.

[0076] A method and/or a composition for reducing stretch marks of the
skin, comprising:

applying to the skin, preferably at least to the portion of the skin
showing stretchmarks, a composition comprising the compound of formula I
at least once a day for a period of time at least sufficient to provide a
reduction of the visible signs of stretch marks. The period of time at
least sufficient to provide the reduction of the visible signs of stretch
marks generally is between one day and 12 months, preferably three days
and six months, more preferably between two weeks and two months.

[0077] A method and/or a composition for reducing stretch marks of the
skin, comprising:

applying to the skin, preferably at least to the portion of the skin
showing stretch marks, a composition comprising the compound of formula I
at least once a day for a period of time at least sufficient, to provide
a reduction of the visible signs of stretch marks. The period of time at
least sufficient to provide the reduction of the visible signs of stretch
marks generally is between one day and 12 months, preferably three days
and six months, more preferably between two weeks and two months.

[0078] A method and/or a composition for reducing dark circles under the
eyes, comprising:

applying to the skin, preferably at least to the portion of the skin
showing the dark circles, a composition comprising the compound of
formula I at least once a day for a period of time at least sufficient to
provide a reduction of the dark circles of the portion of human skin. The
period of time at least sufficient to provide the reduction of the dark
circles generally is between one day and 12 months, preferably three days
and six months, more preferably between two weeks and two months.

[0079] One aspect of the present invention relates to the use of the
compound of formula I for the protection of the skin against hair
treatment agents, especially, for the protection of the skin of the head
against pigments, dyestuffs, dyes and/or colouring agents which are
commonly used for colouring of the hair. During the treatment of the hair
with cosmetic compositions the contact of the head treatment composition
with the underlying skin is normally not completely avoidable. The
contact of the head treatment composition with the underlying skin is
especially disadvantageous in the case of hair colouring compositions,
since the resulting colouration of the parts of the skin around the hair
line and/or the roots of the hair is generally regarded as unesthetic and
thus undesirous.

[0080] Thus, it is desirous to protect the skin from the negative effects
of the hair treatment compositions. It is known in the art to use a
variety compositions, such as emulsions, or other agents, such as
vaseline, to achieve such a protection of the skin. However, the
compositions and agents of prior art show only limited efficacy and/or
have two be removed after the application of the head treatment
composition. For example, vaseline is hard to remove from the skin and/or
a hair due to its insolubility in water. For a sufficient removal
thereof, the use of strong detergents and/or organic solvents can become
necessary, thereby affecting the intended result of the application of
the hair treatment composition and/or having negative effect on the
condition of the skin and/or hair.

[0081] According to the instant invention, the compound of formula I can
be advantageously applied to protect the skin against hair treatment
agents and especially to protect the skin of the head against adverse
effects of pigments, dyestuffs, dyes and/or colouring agents, or hair
colouring compositions in general.

[0082] Thus, a further subject of the instant invention is:

[0083] The use of the compound of formula I as described above/below for
the protection of the skin against hair treatment agents, especially for
the protection of the skin of the head against pigments, dyestuffs, dyes
and/or colouring agents, or hair colouring compositions in general.

[0084] The use of the compound of formula I in a composition for the
protection of the skin against hair treatment agents, especially for the
protection of the skin of the head against pigments, dyestuffs, dyes
and/or colouring agents, or hair colouring compositions in general.

[0085] The use of the compound of formula I for producing a preparation to
protect the skin against hair-treatment compositions, preferably
compositions which can dye, tint, shape, harden, condition, soften,
repair or style hair, and especially compositions which can colour or
tint the hair.

[0086] The use of the compound of formula I for the simultaneous
protection of the skin against hair-treatment compositions and
additionally for the care of the skin.

[0087] The compositions of the invention generally comprise the compound
of formula I and one or more vehicle or carrier, preferably one or more
cosmetically acceptable vehicle or carrier. The one or more vehicles or
carriers may be independently selected from the group of hydrophobic and
hydrophilic vehicles or carriers. Suitable, hydrophobic vehicles or
carriers include, for example, waxy non-ionic substances, preferably waxy
non-ionic substances commonly used, in cosmetics, including, but not
limited to esters and ethers of fatty alcohols and of fatty acids, with
carbon chain length from C4 to C22, preferably from C8 to
C18, and most preferably from C12 to C18. Examples of a
fatty hydrophobic carriers or vehicles are preferably selected from the
group consisting of isopropyl myristate, isopropyl palmitate, octyl
palmitate, isopropyl lanolate, acetylated lanolin alcohol, the benzoate
of C12 to C15 alcohols, cetearyl octanoate, cetyl palmitate,
myristyl myristate, myristyl lactate, cetyl acetate, propylene glycol
dicaprylate/caprate, decyl oleate, acetylated lanolin, stearyl
heptanoate, diisostearyl malate, octyl hydroxystearate, octyl
hydroxystearate, and isopropyl isostearate, and the like. Examples of
hydrophilic carrier or vehicles, especially for solutions, are preferably
selected from the group consisting of glycols and alkoxylated glycols,
preferably glycols and alkoxylated glycols commonly used in cosmetics,
including, but not limited to, ethylene glycol, diethylene glycol,
triethylene glycol, propylene glycol, dipropylene glycol, and the like.

[0088] The compositions according to the invention, especially the
cosmetic compositions according to the invention may be formulated as
creams, lotions, serums, sprays, sticks and other forms known to those
skilled in the art. Creams and lotions are the currently preferred
product forms.

[0089] Preferably, the concentration of the compound of formula I in the
cosmetically acceptable vehicle may range from 1 ppb to 10,000 ppm,
preferably from 10 ppb to 1,000 ppm, more preferably from 100 ppb to 100
ppm, and most preferably from 1 ppm to 100 ppm.

[0090] Preferably, cosmetic compositions can typically comprise the
carrier solution described above at levels between about 0.01% and about
90% by weight, preferably between about 0.1% and about 50%, more
preferably between about 0.1% and about 20%, and more preferred still
between about 1% and about 10% by weight.

[0091] Preferably, the concentration of the compound of formula I in the
composition for application, preferably application to the skin and/or
hair, may range from 1 ppb to 10,000 ppm, preferably from 10 ppb to 1,000
ppm, more preferably from 100 ppb to 100 ppm, even more preferably from
0.5 ppm to 150 ppm and most preferably 1 ppm to 100 ppm, for example
about 0.5 ppm, about 1 ppm, about 1.5 ppm, about 5 ppm, about 10 ppm,
about 25 ppm, about 50 ppm, about 75 ppm, about 100 ppm or about 125 ppm.

[0092] If applicable, ppb and ppm preferably are to be regarded to be
based on the respective weights, such as of the weight of the respective
components (e.g. compound of formula I, vehicle) and/or the weight of the
respective component and the total weight of the composition.
Accordingly, 1 ppm is preferably regarded as 1 mg/kg or 10-4% by
weight.

[0094] The invention also provides a method for ameliorating and/or
preventing signs of human skin photo- and intrinsic aging comprising
topically applying the cosmetic compositions of the invention. The
cosmetic compositions of the invention are preferably applied to affected
skin areas once or twice daily for as long as is necessary to achieve
desired anti-aging results.

[0095] The present invention furthermore relates to compositions,
preferably non-therapeutic compositions, comprising the compound of
formula I and at least one further skin-care ingredient and at least one
carrier which is suitable for topical applications, and to the use of the
above-mentioned compounds for the care, preservation or improvement of
the general state of the skin or hair.

[0096] Uses which are preferred in accordance with the invention are, in
particular, the use for prophylaxis against time- and/or light-induced
ageing processes of the human skin or human hair, in particular for
prophylaxis against dry skin, wrinkle formation and/or pigment defects,
and/or for the reduction or prevention of the harmful effects of UV rays
on the skin, and for prophylaxis against or reduction of skin unevenness,
such as wrinkles, fine lines, rough skin, or large-pored skin.

[0097] Uses which are preferred in accordance with the invention are
furthermore the use for the prophylaxis and/or prevention of premature
skin ageing, in particular for the prophylaxis and/or prevention of
light- or ageing-induced wrinkling of the skin, for the reduction of
pigmentation and keratosis actinica, and for the prophylaxis and/or
treatment of all diseases which are associated with normal skin ageing or
light-induced ageing of the skin, and for the prophylaxis and/or
treatment of skin diseases which are associated with defective
keratinisation relating to differentiation and cell proliferation, in
particular for the treatment of acne vulgaris, acne comedonica,
polymorphic acne, acne rosaceae, nodular acne, acne conglobata,
age-related acne, acne occurring as a side effect, such as acne solaris,
medicament-related acne or acne professionalis, for the treatment of
other defects of keratinisation, in particular ichthyosis, ichthyosiform
states, Darier's disease, keratosis palmoplantaris, leukoplakia,
leukoplakiform states, skin and mucosal (buccal) eczema (lichen), for the
treatment of other skin diseases which are associated with defective
keratinisation and have an inflammatory and/or immunoallergic component,
and in particular all forms of psoriasis relating to the skin, mucous
membranes and finger- and toenails, and psoriatic rheumatism and skin
atopy, such as eczema, or respiratory atopy, or also hypertrophy of
the'gums, and for the prophylaxis and/or treatment of all benign or
malignant excrescence of the dermis or epidermis, which may be of viral
origin, such as verruca vulgar's, verruca plana, epidermodysplasia
verruciformis, oral papillomatosis, papillomatosis florida, and
excrescence which may be caused by UV radiation, in particular
epithelioma baso-cellulare and epithelioma spinocellulare.

[0098] The present invention also relates to the use of the compound of
formula I for the preparation of compositions which are suitable for the
above-mentioned uses.

[0099] The compositions here are preferably non-therapeutical, more
preferably either compositions which can be used topically, for example
cosmetic or dermatological formulations, or foods or food supplements. In
this case, the compositions comprise a cosmetically or dermatologically
or food-suitable carrier and, depending on the desired property profile,
optionally further suitable ingredients.

[0100] The use according to the invention of the compound of formula I in
compositions offers, inter alia, protection against damage caused
directly or indirectly by UV radiation or by processes caused by reactive
compounds, such as, for example, skin ageing, loss of skin moisture, loss
of skin elasticity, formation of wrinkles or lines or of pigment defects
or age spots.

[0101] The present invention furthermore relates to the use of the
above-mentioned compositions for the prevention of undesired changes in
the skin picture, such as, for example, acne or greasy skin, keratoses,
light-sensitive, inflammatory, erythematous, allergic or
autoimmune-reactive reactions.

[0102] However, the compound of formula I and compositions according to
the invention preferably also serve for calming sensitive and irritated
skin, for the preventative regulation of collagen, hyaluronic acid and
elastin synthesis, stimulation of DNA synthesis, in particular in the
case of deficient or hypoactive skin states, regulation of the
transcription and translation of matrix-degrading enzymes, in particular
of MMPs, increasing cell regeneration and regeneration of the skin,
increasing the skin's own protective and repair mechanisms for DNA,
lipids and/or proteins.

[0103] The compound of formula I is typically employed in accordance with
the 1.0 invention in amounts of from 0.01 to 20% by weight, preferably in
amounts of from 0.1% by weight to 10% by weight and particularly
preferably in amounts of from 1 to 8% by weight. The person skilled in
the art has absolutely no difficulties in selecting the amount
correspondingly depending on the intended action of the composition.

[0104] The protective action against oxidative stress or against the
effect of free radicals can thus be further improved if the compositions
comprise one or more further antioxidants, where the person skilled in
the art has absolutely no difficulties in selecting antioxidants having a
suitably fast or time-delayed action.

[0105] In a preferred embodiment of the present invention, at least one
further skin-care ingredient is one or more antioxidants and/or vitamins.

[0107] Suitable antioxidants are furthermore described in WO 2006/111233
and WO 2006/111234.

[0108] Suitable antioxidants are also compounds of the general formula A
and/or B

##STR00003##

wherein [0109] R1 is selected from the group consisting of
--C(O)CH3--CO2R3, --C(O)NH2 and
--C(O)N(R4)2, [0110] X is O or NH, [0111] R2 is linear or
branched Alkyl having 1 to 30 C-atoms, [0112] R3 is linear or
branched Alkyl having 1 to 20 C-atoms, [0113] R4 is in each case
independently selected from the group consisting of H and linear or
branched Alkyl having 1 to 8 C-atoms, [0114] R5 is selected from the
group consisting of linear or branched Alkyl having 1 to 8 C-atoms and
linear or branched Alkoxy having 1 to 8 C-atoms and [0115] R6 is
selected from the group consisting of linear or branched Alkyl mit 1 to 8
C-atoms bedeutet, preferably selected from derivatives of the
2-(4-Hydroxy-3,5-dimethoxybenzyliden)-malonic acid and/or
2-(4-Hydroxy-3,5-dimethoxybenzyl)-malonic acid, and especially preferably
selected from 2-(4-Hydroxy-3,5-dimethoxybenzyliden)-malonic
acid-bis-(2-ethylhexyl)ester (z.B. Oxynex® ST Liquid) and/or
2-(4-Hydroxy-3,5-dimethoxybenzyl)-malonic acid-bis-(2-ethylhexyl)ester
(z.B. RonaCare® AP).

[0116] Mixtures of antioxidants are likewise suitable for use in the
cosmetic compositions according to the invention. Known and commercial
mixtures are, for example, mixtures comprising, as active ingredients,
lecithin, L-(+)-ascorbyl palmitate and citric acid (for example
Oxynex® AP), natural tocopherols, L-(+)-ascorbyl palmitate,
L-(+)-ascorbic acid and citric acid (for example Oxynex® K LIQUID),
tocopherol extracts from natural, sources, L-(+)-ascorbyl palmitate,
L-(+)-ascorbic acid and citric acid (for example Oxynex® L LIQUID),
DL-α-tocopherol, L-(+)-ascorbyl palmitate, citric acid and lecithin
(for example Oxynex® LM) or butylhydroxytoluene (BHT), L-(+)-ascorbyl
palmitate and citric acid (for example Oxynex® 2004). Antioxidants of
this type are usually employed with the compound of formula I in
compositions of this type in ratios in the range from 1000:1 to 1:1000,
preferably in amounts of from 100:1 to 1:100.

[0118] Of the phenols having an antioxidative action, the polyphenols,
some of which are naturally occurring, are of particular interest for
applications in the pharmaceutical, cosmetic or nutrition sector. For
example, the flavonoids or bioflavonoids, which are principally known as
plant dyes, frequently have an antioxidant potential. K. Lemanska, H.
Szymusiak, B. Tyrakowska, R. Zielinski, I. M. C. M. Rietjens; Current
Topics in Biophysics 2000, 24(2), 101-108, are concerned with effects of
the substitution pattern of mono- and dihydroxy-flavones. It is observed
therein that dihydroxyflavones containing an OH group adjacent to the
keto function or OH groups in the 3',4'- or 6,7- or 7,8-position have
antioxidative properties, while other mono- and dihydroxyflavones in some
cases do not have antioxidative properties.

[0120] Suitable antioxidants are furthermore compounds of the formula II

##STR00004##

where R1 to R10 may be identical or different and are selected
from [0121] H [0122] OR11[0123] straight-chain or branched
C1- to C20-alkyl groups, [0124] straight-chain or branched
C3- to C20-alkenyl groups, [0125] straight-chain or branched
C1- to C20-hydroxyalkyl groups, where the hydroxyl group may be
bonded to a primary or secondary carbon atom of the chain and furthermore
the alkyl chain may also be interrupted by oxygen, and/or [0126]
C3-- to C10-cycloalkyl groups and/or C3- to
C12-cycloalkenyl groups, where the rings may each also be bridged by
--(CH2)n-- groups, where n=1 to 3, [0127] where all OR11
are, independently of one another, [0128] OH [0129] straight-chain or
branched C1- to C20-alkoxy groups, [0130] straight-chain or
branched C3- to C20-alkenyloxy groups, [0131] straight-chain or
branched C1- to C20-hydroxyalkoxy groups, where the hydroxyl
group(s) may be bonded to a primary or secondary carbon atom of the chain
and furthermore the alkyl chain may also be interrupted by oxygen, and/or
[0132] C3-- to C10-cycloalkoxy groups and/or C3- to
C12-cycloalkenyloxy groups, where the rings may each also be bridged
by --(CH2)n-- groups, where n=1 to 3, and/or [0133] mono-
and/or oligoglycosyl radicals, [0134] with the proviso that at least 4
radicals from R1 to R7 are OH and that the molecule contains at
least two pairs of adjacent --OH groups, [0135] or R2, R5 and
R6 are OH and the radicals R1, R3, R4 and R7-10
are H, as described in the earlier. German patent application DE
10244282.7.

[0136] Besides the advantages mentioned above, the advantages of the
compositions according to the invention comprising at least one
antioxidant here are, in particular, the antioxidant action and the good
skin tolerability. In addition, the compounds described here are
preferably colourless or have only a weak colour and thus only result in
slight discoloration of the compositions, or none at all.

[0137] Of particular advantage are compositions, preferably
non-therapeutic compositions, comprising at least one compound of the
formula II which is characterised in that at least two adjacent radicals
of the radicals R1 to R4 are OH and at least two adjacent
radicals of the radicals R5 to R7 are OH. Particularly
preferred compositions comprise at least one compound of the formula II
which is characterised in that at least three adjacent radicals of the
radicals R1 to R4 are OH, preferably with the radicals R1
to R3 being. OH.

[0138] It is also advantageous to administer the compounds of the formula
II in encapsulated form, for example as cellulose or chitin capsules, in
gelatine or wax matrices or encapsulated with cyclodextrins.

[0139] In particular, preferred compositions according to the invention
are also suitable for the treatment of skin diseases associated with a
defect in keratinisation which affects differentiation and cell
proliferation, in particular for the treatment of acne vulgaris, acne
comedonica, polymorphic acne, acne rosaceae, nodular acne, acne
conglobata, age-induced acne, acne which arises as a side effect, such as
acne solaris, medicament-induced acne or acne professionalis, for the
treatment of other defects in keratinisation, in particular ichthyosis,
ichthyosiform states, Darier's disease, keratosis palmoplantaris,
leucoplasia, leucoplasiform states, herpes of the skin and mucous
membrane (buccal) (lichen), for the treatment of other skin diseases
associated with a defect in keratinisation and which have an inflammatory
and/or immunoallergic component and in particular all forms of psoriasis
which affect the skin, mucous membranes and fingers and toenails, and
psoriatic rheumatism and skin atopy, such as eczema or respiratory atopy,
or hypertrophy of the gums, it furthermore being possible for the
compounds to be used for some inflammations which are not associated with
a defect in keratinisation, for the treatment of all benign or malignant
excrescence of the dermis or epidermis, which may be of viral origin,
such as verruca vulgaris, verruca plana, epidermodysplasia verruciformis,
oral papillomatosis, papillomatosis florida, and excrescence which may be
caused by UV radiation, in particular epithelioma baso-cellulare and
epithelioma spinocellulare, for the treatment of other skin diseases,
such as dermatitis bullosa and diseases affecting the collagen, for the
treatment of certain eye diseases, in particular corneal diseases, for
overcoming or combating light-induced skin ageing associated with ageing,
for reducing pigmentation and keratosis actinica and for the treatment of
all diseases associated with normal ageing or light-induced ageing, for
the prevention or healing of wounds/scars of atrophy of the epidermis
and/or dermis caused by locally or systemically applied corticosteroids
and all other types of skin atrophy, for the prevention or treatment of
defects in wound healing, for the prevention or elimination of stretch
marks caused by pregnancy or for the promotion of wound healing, for
combating defects in tallow production, such as hyperseborrhoea in acne
or simple seborrhoea, for combating or preventing cancer-like states or
pre-carcinogenic states, in particular promyelocytic leukaemia, for the
treatment of inflammatory diseases, such as arthritis, for the treatment
of all virus-induced diseases of the skin or other areas of the body, for
the prevention or treatment of alopecia, for the treatment of skin
diseases or diseases of other areas of the body with an immunological
component, for the treatment of cardiovascular diseases, such as
arteriosclerosis or hypertension, and of non-insulin-dependent diabetes,
and for the treatment of skin problems caused by UV radiation.

[0140] Compositions which are particularly preferred in accordance with
the invention also comprise UV filters besides the compound of formula I.

[0141] In principle, all UV filters are suitable for combination with the
compound of formula I. Particular preference is given to UV filters whose
physiological acceptability has already been demonstrated. Both for UVA
and UVB filters, there are many proven substances which are known from
the specialist literature, for example:

[0160] Through combination of the compound of formula I with further UV
filters, the protective action against harmful influences of UV radiation
can be optimised.

[0161] Optimised compositions may comprise, for example, the combination
of the organic UV filters 4'-methoxy-6-hydroxyflavone with
1-(4-tert-butylphenyl)-3-(4-methoxyphenyl)propane-1,3-dione and
3-(4'-methylbenzylidene)-dl-camphor.

[0162] This combination gives rise to broad-band protection, which can be
supplemented by the addition of inorganic UV filters, such as titanium
dioxide micro-particles.

[0163] All the said UV filters can also be employed in encapsulated form.
In particular, it is advantageous to employ organic UV filters in
encapsulated form. In detail, the following advantages arise: [0164]
The hydrophilicity of the capsule wall can be set independently of the
solubility of the UV filter. Thus, for example, it is also possible to
incorporate hydrophobic UV filters into purely aqueous compositions. In
addition, the oily impression on application of the composition
comprising hydrophobic UV filters, which is frequently regarded as
unpleasant, is suppressed. [0165] Certain UV filters, in particular
dibenzoylmethane derivatives, exhibit only reduced photostability in
cosmetic compositions. Encapsulation of these filters or compounds which
impair the photostability of these filters, such as, for example,
cinnamic acid derivatives, enables the photostability of the entire
composition to be increased. [0166] Skin penetration by organic UV
filters and the associated potential for irritation on direct application
to the human skin is repeatedly being discussed in the literature. The
encapsulation of the corresponding substances which is proposed here
suppresses this effect. [0167] In general, encapsulation of individual UV
filters or other ingredients enables composition problems caused by the
interaction of individual composition constituents with one another, such
as crystallisation processes, precipitation and agglomerate formation, to
be avoided since the interaction is suppressed.

[0168] It is therefore preferred in accordance with the invention for one
or more of the above-mentioned UV filters to be in encapsulated form. It
is advantageous here for the capsules to be so small that they cannot be
viewed with the naked eye. In order to achieve the above-mentioned
effects, it is furthermore necessary for the capsules to be sufficiently
stable and the encapsulated active ingredient (UV filter) only to be
released to the environment to a small extent, or not at all.

[0169] Suitable capsules can have walls of inorganic or organic polymers.
For example, U.S. Pat. No. 6,242,099 B1 describes the production of
suitable capsules with walls of chitin, chitin derivatives or
polyhydroxylated polyamines. Capsules which can particularly preferably
be employed in accordance with the invention have walls which can be
obtained by a sol-gel process, as described in the applications WO
00/09652 WO 00/72806 and WO 00/71084. Preference is again given here to
capsules whose walls are built up from silica gel (silica; undefined
silicon oxide hydroxide). The production of corresponding capsules is
known to the person skilled in the art, for example from the cited patent
applications, whose contents expressly also belong to the subject-matter
of the present application.

[0170] The capsules are preferably present in compositions according to
the invention in amounts which ensure that the encapsulated UV filters
are present in the composition in the above-indicated amounts.

[0171] The skin-protecting or skin-care active ingredients can in
principle be any active ingredients known to the person skilled in the
art.

[0172] In an embodiment of the present invention, particularly preferred
active ingredients are pyrimidinecarboxylic acids and/or aryl oximes.
Pyrimidinecarboxylic acids occur in halophilic microorganisms and play a
role in osmoregulation of these organisms (EA. Galinski et al., Eur. J.
Biochem., 149 (1985) pages 135-139). Of the pyrimidinecarboxylic acids,
particular mention should be made here of ectoine
((S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidine-carboxylic acid) and
hydroxyectoine
((S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidinecarboxylic acid)
and derivatives thereof. These compounds stabilise enzymes and other
biomolecules in aqueous solutions and organic solvents. Furthermore, they
stabilise, in particular, enzymes against denaturing conditions, such as
salts, extreme pH values, surfactants, urea, guanidinium chloride and
other compounds.

[0173] Ectoine and ectoine derivatives, such as hydroxyectoine, can
advantageously be used in medicaments. In particular, hydroxyectoine can
be employed for the preparation of a medicament for the treatment of skin
diseases. Other areas of application of hydroxyectoine and other ectoine
derivatives are typically in areas in which, for example, trehalose is
used as additive. Thus, ectoine derivatives, such as hydroxyectoine, can
be used as, protectant in dried yeast and bacteria cells. Pharmaceutical
products, such as non-glycosylated, pharmaceutically active peptides and
proteins, for example t-PA, can also be protected with ectoine or its
derivatives.

[0174] Of the cosmetic applications, particular mention should be made of
the use of ectoine and ectoine derivatives for the care of aged, dry or
irritated skin. Thus, European patent application EP-A-0 671 161
describes, in particular, that ectoine and hydroxyectoine are employed in
cosmetic compositions, such as powders, soaps, surfactant-containing
cleansing products, lipsticks, rouge, make-ups, care creams and sunscreen
compositions.

[0175] Preference is given here to the use of a pyrimidinecarboxylic acid
of following formula III

##STR00005##

in which [0176] R1 is a radical H or C1-8-alkyl, [0177] R2 is a
radical H or C1-4-alkyl, [0178] and [0179] R3, R4, R5 and
R6 are each, independently of one another, a radical from the group
consisting of H, OH, NH2 and C1-4-alkyl. Preference is given to the
use of pyrimidinecarboxylic acids in which R2 is a methyl or ethyl
group, and R1 or R5 and R6 are H.

[0180] Particular preference is given to the use of the
pyrimidinecarboxylic acids ectoine
((S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) and
hydroxyectoine
((S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidine-carboxylic
acid). The compositions according to the invention preferably comprise
pyrimidinecarboxylic acids of this type in amounts, of up to 15% by
weight. The pyrimidinecarboxylic acids are preferably employed here in
ratios of from 100:1 to 1:100 with respect to the compound of formula I
with ratios in the range from 1:10 to 10:1 being particularly preferred.

[0181] Of the aryl oximes, preference is given to the use of
2-hydroxy-5-methyllauro-phenone oxime, which is also known as HMLO, LPO
or F5. Its suitability for use in cosmetic compositions is disclosed, for
example, in DE-A-41 16 123. Compositions which comprise
2-hydroxy-5-methyllaurophenone oxime are accordingly suitable for the
treatment of skin diseases which are accompanied by inflammation. It is
known that compositions of this type can be used, for example, for the
therapy of psoriasis, various forms of eczema, irritative and toxic
dermatitis, UV dermatitis and further allergic and/or inflammatory
diseases of the skin and integumentary appendages. Compositions according
to the invention which, in addition to the compound of formula I
additionally comprise an aryl oxime, preferably
2-hydroxy-5-methyllaurophenone oxime, exhibit surprising antiinflammatory
suitability. The compositions here preferably comprise from 0.01 to 10%
by weight of the aryl oxime, it being particularly preferred for the
composition to comprise from 0.05 to 5% by weight of aryl oxime.

[0182] All compounds or components which can be used in the compositions
are either known or commercially available or can be synthesised by known
processes. The preparation of the compound of formula I is described in
U.S. Pat. No. 6,596,758 B1 as Example 16.

[0183] The compound of formula I can be incorporated into cosmetic or
dermatological compositions in the customary manner. Suitable
compositions are those for external use, for example in the form of a
cream, lotion or gel or as a solution which can be sprayed onto the skin.
Suitable for internal use are administration forms such as capsules,
coated tablets, powders, tablet solutions or solutions.

[0184] Use forms of the compositions according to the invention that may
be mentioned are, for example, solutions, suspensions, emulsions, PIT
emulsions, pastes, ointments, gels, creams, lotions, powders, soaps,
surfactant-containing cleansing preparations, oils, aerosols and sprays.
Examples of other use forms are sticks, shampoos and shower compositions.
Any desired customary carriers, assistants and, if desired, further
active ingredients may be added to the composition.

[0185] Preferred assistants originate from the group consisting of
preservatives, an anti-oxidants, stabilisers, solubilisers, vitamins,
colorants and odour improvers.

[0192] Face and body oils may comprise the customary carriers, such as
synthetic oils, such as fatty acid esters, fatty alcohols, silicone oils,
natural oils, such as vegetable oils and oily plant extracts, paraffin
oils or lanolin oils, or mixtures of these substances.

[0194] The preferred composition forms according to the invention include,
in particular, emulsions.

[0195] Emulsions according to the invention are advantageous and comprise,
for example, the said fats, oils, waxes and other fatty substances, as
well as water and an emulsifier, as usually used for a composition of
this type.

[0196] The lipid phase may advantageously be selected from the following
group of substances: [0197] mineral oils, mineral waxes; [0198] oils,
such as triglycerides of capric or caprylic acid, furthermore natural
oils, such as, for example, castor oil; [0199] fats, waxes and other
natural and synthetic fatty substances, preferably esters of fatty acids
with alcohols having a low carbon number, for example with isopropanol,
propylene glycol or glycerol, or esters of fatty alcohols with alkanoic
acids having a low carbon number or with fatty acids; [0200] silicone
oils, such as dimethylpolysiloxanes diethylpolysioxanes,
diphenylpolysiloxanes and mixed forms thereof.

[0201] For the purposes of the present invention, the oil phase of the
emulsions, oleo-gels or hydrodispersions or lipodispersions is
advantageously selected from the group consisting of esters of saturated
and/or unsaturated, branched and/or unbranched alkanecarboxylic acids
having a chain length of from 3 to 30 carbon atoms and saturated and/or
unsaturated, branched and/or unbranched alcohols having a chain length of
from 3 to 30 carbon atoms, or from the group consisting of esters of
aromatic carboxylic acids and saturated and/or unsaturated, branched
and/or unbranched alcohols having a chain length of from 3 to 30 carbon
atoms. Ester oils of this type can then advantageously be selected from
the group consisting of isopropyl myristate, isopropyl palmitate,
isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate,
n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl
isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl
stearate, 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl
oleate, erucyl erucate and synthetic, semi-synthetic and natural mixtures
of esters of this type, for example jojoba oil.

[0202] The oil phase may furthermore advantageously be selected from the
group consisting of branched and unbranched hydrocarbons and waxes,
silicone oils, dialkyl ethers, or the group consisting of saturated and
unsaturated, branched and unbranched alcohols, and fatty acid
triglycerides, specifically the triglycerol esters of saturated and/or
unsaturated, branched and/or unbranched alkane-carboxylic acids having a
chain length of from 8 to 24, in particular 12 to 18, carbon atoms. The
fatty acid triglycerides may advantageously be selected, for example,
from the group consisting of synthetic, semi-synthetic and natural oils,
for example olive oil, sunflower oil, soya oil, peanut oil, rapeseed oil,
almond oil, palm oil, coconut oil, palm kernel oil and the like.

[0203] Any desired mixtures of oil and wax components of this type may
also advantageously be employed for the purposes of the present
invention. It may also be advantageous to employ waxes, for example cetyl
palmitate, as the only lipid component of the oil phase.

[0205] Particularly advantageous are mixtures of C12-15-alkyl
benzoate and 2-ethylhexyl isostearate, mixtures of C12-15-alkyl
benzoate and isotridecyl isononanoate, as well as mixtures of
C12-15-alkyl benzoate, 2-ethylhexyl isostearate and isotridecyl
isononanoate.

[0206] Of the hydrocarbons, paraffin oil, squalane and squalene may
advantageously be used for the purposes of the present invention.

[0207] Furthermore, the oil phase may also advantageously have a content
of cyclic or linear silicone oils or consist entirely of oils of this
type, although it is preferred to use an additional content of other
oil-phase components in addition to the silicone oil or the silicone
oils.

[0208] The silicone oil to be used in accordance with the invention is
advantageously cyclomethicone (octamethylcyclotetrasiloxane). However, it
is also advantageous for the purposes of the present invention to use
other silicone oils, for example hexamethylcyclotrisiloxane,
polydimethylsiloxane or poly(methylphenylsiloxane).

[0209] Also particularly advantageous are mixtures of cyclomethicone and
isotridecyl isononanoate and of cyclomethicone and 2-ethylhexyl
isostearate.

[0210] The aqueous phase of the compositions according to the invention
optionally advantageously comprises alcohols, diols or polyols having a
low carbon number, and ethers thereof, preferably ethanol, isopropanol,
propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or
monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl
ether, diethylene glycol monomethyl or monoethyl ether and analogous
products, furthermore alcohols having a low carbon number, for example
ethanol, isopropanol, 1,2-propanediol or glycerol, and, in particular,
one or more thickeners, which may advantageously be selected from the
group consisting of silicon dioxide, aluminium silicates, polysaccharides
and derivatives thereof, for example hyaluronic acid, xanthan gum,
hydroxypropylmethylcellulose, particularly advantageously from the group
consisting of the polyacrylates, preferably a polyacrylate from the group
consisting of the so-called Carbopols, for example Carbopol grades 980,
981, 1382, 2984 or 5984, in each case individually or in combination.

[0211] In particular, mixtures of the above-mentioned solvents are used.
In the case of alcoholic solvents, water may be a further constituent.

[0212] Emulsions according to the invention are advantageous and comprise,
for example, the said fats, oils, waxes and other fatty substances, as
well as water and an emulsifier, as usually used for a formulation of
this type.

[0213] In a preferred embodiment, the compositions according to the
invention comprise hydrophilic surfactants.

[0214] The hydrophilic surfactants are preferably selected from the group
consisting of the alkylglucosides, acyl lactylates, betaines and coconut
amphoacetates.

[0215] The alkylglucosides are themselves advantageously selected from the
group consisting of the alkylglucosides which are distinguished by the
structural formula

##STR00006## [0216] where [0217] R is a branched or unbranched alkyl
radical having from 4 to 24 carbon atoms, and where DP denotes a mean
degree of glucosylation of up to 2.

[0218] The value DP represents the degree of glucosidation of the
alkylglucosides used in accordance with the invention and is defined as

[0219] Products which are advantageous according to the invention are
those having degrees of glucosylation of 1-2, particularly advantageously
of from 1.1 to 1.5, very particularly advantageously of 1.2-1.4, in
particular of 1.3.

[0220] The value DP takes into account the fact that alkylglucosides are
generally, as a consequence of their preparation, in the form of mixtures
of mono- and oligoglucosides. A relatively high content of
monoglucosides, typically in the order of 40-70% by weight, is
advantageous in accordance with the invention.

[0221] Alkylglycosides which are particularly advantageously used for the
purposes of the invention are selected from the group consisting of octyl
glucopyranoside, nonyl glucopyranoside, decyl glucopyranoside, undecyl
glucopyranoside, dodecyl glucopyranoside, tetradecyl glucopyranoside and
hexadecyl glucopyranoside.

[0222] It is likewise advantageous to employ natural or synthetic raw
materials and assistants or mixtures which are distinguished by an
effective content of the active ingredients used in accordance with the
invention, for example Plantaren® 1200 (Henkel KGaA), Oramix® NS
10 (Seppic).

[0223] The acyllactylates are themselves advantageously selected from the
group consisting of the substances which are distinguished by the
structural formula

##STR00007## [0224] where [0225] R1 is a branched or unbranched
alkyl radical having from 1 to 30 carbon atoms, and [0226] M.sup.+ is
selected from the group consisting of the alkali metal ions and the group
consisting of ammonium ions which are substituted by one or more alkyl
and/or one or more hydroxyalkyl radicals, or corresponds to half an
equivalent of an alkaline earth metal ion.

[0227] For example, sodium isostearyl lactylate, for example the product
Pathionic® ISL from the American Ingredients Company, is
advantageous.

[0228] The betaines are advantageously selected from the group consisting
of the substances which are distinguished by the structural formulae

##STR00008## [0229] where [0230] R2 is a branched or unbranched
alkyl radical having from 1 to 30 carbon atoms. [0231] R2 is
particularly advantageously a branched or unbranched alkyl radical having
from 6 to 12 carbon atoms.

[0233] A coconut amphoacetate which is advantageous for the purposes of
the invention is, for example, sodium coconut amphoacetate, as available
under the name Miranol® Ultra C32 from Miranol Chemical Corp.

[0234] The compositions according to the invention are advantageously
characterised in that the hydrophilic surfactant(s) is (are) present in
concentrations of 0.01-20% by weight, preferably 0.05-10% by weight,
particularly preferably 0.1-5% by weight, in each case based on the total
weight of the composition.

[0235] For use, the cosmetic and dermatological compositions are applied
in sufficient amount to the skin and/or hair in the usual manner for
cosmetics.

[0236] Cosmetic and dermatological compositions according to the invention
may exist in various forms. Thus, they may be, for example, a solution, a
water-free composition, an emulsion or microemulsion of the water-in-oil
(W/O) or oil-in-water (O/W) type, a multiple emulsion, for example of the
water-in-oil-in-water (W/O/W) type, a gel, a solid stick, an ointment or
an aerosol. It is also advantageous to administer ectoines in
encapsulated form, for example in collagen matrices and other
conventional encapsulation materials, for example as cellulose
encapsulations, in gelatine, wax matrices or liposomally encapsulated. In
particular, wax matrices, as described in DE-A 43 08 282, have proven
favourable. Preference is given to emulsions. O/W emulsions are
particularly preferred. Emulsions, W/O emulsions and O/W emulsions are
obtainable in a conventional manner.

[0237] Emulsifiers that can be used are, for example, the known W/O and
O/W emulsifiers. It is advantageous to use further conventional
co-emulsifiers in the preferred O/W emulsions according to the invention.

[0238] Co-emulsifiers which are advantageous according to the invention
are, for example, O/W emulsifiers, principally from the group consisting
of the substances having HLB values of 11 to 16, very particularly
advantageously having HLB values of 14.5 to 15.5, so long as the O/W
emulsifiers have saturated radicals R and R'. If the O/W emulsifiers have
unsaturated radicals R and/or R' or in the case of isoalkyl derivatives,
the preferred HLB value of such emulsifiers may also be lower or higher.

[0241] An ethoxylated alkyl ether carboxylic acid or salt thereof which
can advantageously be used is sodium laureth-11 carboxylate. An alkyl
ether sulfate which can advantageously be used is sodium laureth-14
sulfate. An ethoxylated cholesterol derivative which can advantageously
be used is polyethylene glycol (30) cholesteryl ether. Polyethylene
glycol (25) soyasterol has also proven successful. Ethoxylated
triglycerides which can advantageously be used are the polyethylene
glycol (60) evening primrose glycerides.

[0246] Preferred compositions according to the invention are particularly
suitable for protecting human skin against ageing processes and against
oxidative stress, i.e. against damage by free radicals, as are produced,
for example, by sunlight, heat or other influences. In this connection,
they are in the various administration forms usually used for this
application. For example, they may, in particular, be in the form of a
lotion or emulsion, such as in the form of a cream or milk (O/W, W/O,
O/W/O, W/O/W), in the form of oily-alcoholic, oily-aqueous or
aqueous-alcoholic gels or solutions, in the form of solid sticks or may
be formulated as an aerosol.

[0247] The composition may comprise cosmetic adjuvants which are usually
used in this type of composition, such as, for example, thickeners,
softeners, moisturisers, surfactants, emulsifiers, preservatives,
antifoams, perfumes, waxes, lanolin, propellants, dyes and/or pigments
which colour the composition itself or the skin, and other ingredients
usually used in cosmetics.

[0248] The dispersant or solubiliser used can be an oil, wax or other
fatty substance, a lower monoalcohol or lower polyol or mixtures thereof.
Particularly preferred monoalcohols or polyols include ethanol,
isopropanol, propylene glycol, glycerol and sorbitol.

[0249] A preferred embodiment of the invention is an emulsion in the form
of a protective cream or milk which, apart from the compound of formula I
comprises, for example, fatty alcohols, fatty acids, fatty acid esters,
in particular triglycerides of fatty acids, lanolin, natural and
synthetic oils or waxes and emulsifiers in the presence of water.

[0250] Further preferred embodiments are oily lotions based on natural or
synthetic oils and waxes, lanolin, fatty acid esters, in particular
triglycerides of fatty acids, or oily-alcoholic lotions based on a lower
alcohol, such as ethanol, or a glycerol, such as propylene glycol, and/or
a polyol, such as glycerol, and oils, waxes and fatty acid esters, such
as triglycerides of fatty acids.

[0251] The composition according to the invention may also be in the form
of an alcoholic gel which comprises one or more lower alcohols or
polyols, such as ethanol, propylene glycol or glycerol, and a thickener,
such as siliceous earth. The oily-alcoholic gels also comprise natural or
synthetic oil or wax.

[0253] If a composition is formulated as an aerosol, the customary
propellants, such as alkanes, fluoroalkanes and chlorofluoroalkanes, are
generally used.

[0254] The cosmetic composition may also be used to protect the hair
against photochemical damage in order to prevent changes of colour shade,
bleaching or damage of a mechanical nature. In this case, a suitable
formulation is in the form of a rinse-out shampoo, lotion, gel or
emulsion, the composition in question being applied before or after
shampooing, before or after colouring or bleaching or before or after
permanent waving. It is also possible to select a composition in the form
of a lotion or gel for styling or treating the hair, in the form of a
lotion or gel for brushing or blow-waving, in the form of a hair lacquer,
permanent waving composition, colorant or bleach for the hair. Besides
the compound of formula I the composition having light-protection
properties may comprise various adjuvants used in this type of
composition, such as surfactants, thickeners, polymers, softeners,
preservatives, foam stabilisers, electrolytes, organic solvents, silicone
derivatives, oils, waxes, antigrease agents, dyes and/or pigments which
colour the composition itself or the hair, or other ingredients usually
used for hair care.

[0255] The present invention furthermore relates to a process for the
preparation of a composition which is characterised in that the compound
of formula I is mixed with a cosmetically or dermatologically or
food-suitable carrier, and to the use of the compound of formula I for
the preparation of a composition.

[0256] The compositions according to the invention can be prepared here
with the aid of techniques which are well known to the person skilled in
the art.

[0257] The mixing can result in dissolution, emulsification or dispersal
of the compound of formula I.

[0258] The positive effects of the compound of formula I give rise to
their particular suitability for use in cosmetic or pharmaceutical
compositions.

[0259] The properties of the compound of formula I should likewise be
regarded as positive for use in foods or as food supplements or as
functional foods. The further explanations given for foods also apply
correspondingly to food supplements and functional foods.

[0260] The foods which can be enriched with the compound of formula I
include all materials which are suitable for consumption by animals or
consumption by humans, for example vitamins and provitamins thereof,
fats, minerals or amino acids. (The foods may be solid, but also liquid,
i.e. in the form of a beverage).

[0261] The present invention accordingly furthermore relates to the use of
the compound of formula I as food additive for human or animal nutrition,
and to compositions which are foods or food supplements and comprise
corresponding carriers.

[0262] Foods which can be enriched with the compound of formula I are, for
example, also foods which originate from a single natural source, such
as, for example, sugar, unsweetened juice, squash or puree of a single
plant species, such as, for example, unsweetened apple juice (for example
also a mixture of different types of apple juice), grapefruit juice,
orange juice, apple compote, apricot squash, tomato juice, tomato sauce,
tomato puree, etc. Further examples of foods which can be enriched with
the compound of formula I are corn or cereals from a single plant species
and materials produced from plant species of this type, such as, for
example, cereal syrup, rye flour, wheat flour or oat bran. Mixtures of
foods of this type are also suitable for being enriched with the compound
of formula I are, for example, multivitamin preparations, mineral
mixtures or sweetened juice. As further examples of foods which can be
enriched with the compound of formula I, mention may be made of food
compositions, for example prepared cereals, biscuits, mixed drinks, foods
prepared especially for children, such as yoghurt, diet foods,
low-calorie foods or animal feeds.

[0263] The foods which can be enriched with the compound of formula I thus
include all edible combinations of carbohydrates, lipids, proteins,
inorganic elements, trace elements, vitamins, water or active metabolites
of plants and animals.

[0264] The foods which can be enriched with the compound of formula I are
preferably administered orally, for example in the form of meals, pills,
tablets, capsules, powders, syrup, solutions or suspensions.

[0265] The foods according to the invention enriched with the compound of
formula I can be prepared with the aid of techniques which are well known
to the person skilled in the art.

[0266] Due to their action, the is preferable also suitable as medicament
ingredients the compound of formula I can be used, for example, for
preventative treatment of inflammation and allergies of the skin and in
certain cases for preventing certain types of cancer. The compound of
formula I is particularly suitable for the preparation of a medicament
for the treatment of inflammation, allergies and irritation, in
particular of the skin. It is furthermore possible to prepare medicaments
which act as a vein tonic, as cuperose inhibitor, as chemical, physical
or actinic erythema inhibitor, as agent for the treatment of sensitive
skin, as decongestant, as desiccant, as slimming agent, as anti-wrinkle
agent, as stimulator for the synthesis of components of the extracellular
matrix, as strengthening agent for improving skin elasticity, and as
anti-ageing agent. Furthermore, the compound of formula I exhibits
antiallergic and antiinflammatory and antiirritative actions. They are
therefore suitable for the preparation of medicaments for the treatment
of inflammation or allergic reactions.

[0267] The invention is explained in greater detail below by means of
examples. The invention can be carried out throughout the range claimed
and is not restricted to the examples given here.

[0268] Moreover, the following examples are given in order to assist the
skilled artisan to better understand the present invention by way of
exemplification. The examples are not intended to limit the scope of
protection conferred by the claims. The features, properties and
advantages exemplified for the compounds, compositions and/or uses
defined in the examples may be assigned to other compounds, compositions
and/or uses not specifically described and/or defined in the examples,
but falling under the scope of what is defined in the claims.

EXPERIMENTAL

In Vitro Biological Activities

[0269] Analysis of the activation of PPARα and PPARγ is based
on the transfection of a DNA allowing the expression of a reporter gene
(the gene of luciferase) under the control of the PPARs, either
endogenous in the case of PPARγ or exogenous in the case of
PPARα. The reporter plasmid J3TkLuc comprises three copies of the
response element for PPARs of the human apo A-II gene (Staels, 13 et al.
(1995), J. Clin. Invest., 95, 705-712) which are cloned upstream of the
promoter of the thymidine kinase gene of the herpes simplex virus in the
plasmid pGL3. This reporter gene was obtained by subcloning, in the
plasmid pGL3, the plasmid J3TkCAT described above (Fajas, L et al.
(1997), J. Biol. Chem., 272, 18779-18789). The cells used are green
monkey CV1 cells transformed by the SV40 virus, which express PPARγ
(Forman, B. et al. (1995), Cell, 83, 803-812), and human SK-Hep1 cells,
which do not express PPARs. These cells were inoculated at the rate of
20,000 cells per well (96-well plates) and transfected with 150 ng of
reporter DNA complexed with a mixture of lipids. In the case of the
SK-Hep1 cells, an expression vector for PPARα, described by Sher,
T. et al. (1993), Biochemistry, 32, 5598-5604, is cotransfected. After 5
hours, the cells are washed twice and incubated for 36 hours in the
presence of the test compound in a fresh culture medium comprising 10%
foetal calf serum. At the end of incubation, the cells are lysed and the
luciferase activity is measured. This activity is expressed relative to
the control value (data shown in Tables 1a and 1b

[0273] B16-V melanoma cells were incubated for 72 h with assay medium
containing different amounts of test substances. The concentration
depends on the results of the MTT-Assay. Only concentrations without
effect on viability (after 24 h incubation) were used for further melanin
evaluation. Every 24 hours medium was changed and replaced by fresh assay
medium containing the compounds and alpha-MSH (stimulation of melanin
synthesis). The cell number was determined and the cells got lysed using
1M NaOH. Afterwards the amount of melanin was measured at 405 nm with a
microplatereader (Safire2®, Tecan). Different concentrations of
synthetic melanin were used to produce a calibration curve. Melanin
content was expressed as pg/cell.

[0274] The test results are shown in FIG. 1:

[0275] As apparent from FIG. 1 Compound as PPAR-alpha and -gamma agonist
show a superb melanin inhibiting activity. Furthermore the substance is
significantly better than kojic acid.

Formulation Examples

[0276] Formulations for compositions, preferably non-therapeutic
compositions, cosmetic compositions and/or topical compositions,
comprising the compound of formula I are shown by way of example below.
For some commercially available compounds the INCl names are given.
UV-Pearls® OMC stands for the composition with the INCl: water (for
EU: Aqua), Ethylhexyl Methoxycinnamate, Silica, PVP, Chlorphenesin, BHT;
this composition is commercially available under the name Eusolex® UV
Pearl® OMC from Merck KGaA, Darmstadt.

[0277] The other UV Pearl products indicated in the tables are each of
analogous composition with OMC replaced by the UV filter indicated.